| Project/Area Number |
11670424
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Legal medicine
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| Research Institution | University of Tokyo (2000)
Yamaguchi University (1999) |
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Principal Investigator |
UEMURA Koichi University of Tokyo, Graduate School of Research Medicine, Associate, 大学院・医学系研究科, 助手 (30244586)
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| Co-Investigator(Kenkyū-buntansha) |
YASUHARA Masahiro Kyoto Prefectural Faculty of Medicine, Professor University of Medicine, 医学部, 教授 (60305604)
YOSHIDA Ken-ichi University of Tokyo, Graduate School of Professor, Medicine, 大学院・医学系研究科, 教授 (40166947)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2000: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | cell death / PC12 / protein kinase C / apoptosis / methamphetamine / PKC / apoptosis / methamphetamine / 覚醒剤 / ネクローシス / Protein kinase C / glutamate receptor |
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| Research Abstract |
Methamphetamine (MAP) induces schizophrenia-like symptoms and neuronal degeneration of dopaminergic neurons. We studied on the mechanism of MAP-induced cell death with a special reference to apoptosis and PKC (protein kinase C).
MAP induced dose (1-5mM) and time-dependent (6-48hrs) cell death in PC12 cells. The cell death was associated with the increase in the TUNEL staining, while it was inhibited by a broad spectrum caspase inhibitor z-VAD-fmk. However, the cell death is supposed not to be a typical apoptosis because there were neither morphological changes such as nuclear fragmentation or formation of apoptotic bodies nor DNA laddering on agarose gel. The cell death was suppressed by a PKC activator, PMA, but was enhanced by PKC specific inhibitor, calphostin C or bisindolylmaleimide 1. PKC-a, d are not involved as both safingol and rottlerin inhibitor for PKC-α and δ, respectively, did not aggravate MAP-induced cell death. Western blotting analysis demonstrated the translocation of PKC-ε. Antisense oligodeoxynucleotide to PKC-ε aggravated the MAP-induced cell death. The MAP treatment increased PKC activity in the cell lysate. These observations suggest that PKC-ε suppresses the MAP-induced cell death in PC12 cell.
A glutamate receptor may be a PKC target that is involved in the protection against apoptosis after MAP treatment because the antagonist MK801 abrogated all death but the effect was suppressed by PKC inhibition. This effect may be explained by the modulatory effect of PKC on glutamate receptor.
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